Jang Yang Chang

Aurora kinase inhibitors in preclinical and clinical testing

Background: Mitosis is a key step in the cell cycle governing the distribution of genetic material to the daughter cells. Any aberration in this process could lead to genomic instability. Aurora A, B and C, are members of the serine/threonine kinase family. Aurora kinases are essential for spindle assembly, centrosome maturation, chromosomal segregation and cytokinesis during mitosis. Abnormalities in the mitotic process through overexpression/amplification of aurora kinase have been linked to genomic instability leading to tumorigenesis. Hence, use of aurora kinase small molecule inhibitors as potential molecular-targeted therapeutic intervention for cancer is being pursued by various researchers. Objective: To review the literature of aurora kinase inhibitors in clinical and preclinical testing. Method: Pubmed, Scifinder® and www.clinicaltrials.gov databases were used to search the literature for aurora kinase. Conclusion/results: Approximately 13 aurora kinase inhibitors are under Phase I/II evaluation at present for various cancers of different origins; and several others are in preclinical testing. Details of their preclinical/clinical results and important considerations for future aurora kinase inhibitor development are discussed. Considering the fact that aurora kinase plays an important role in the mitosis process and is involved in tumorigenesis, development of aurora kinase inhibitors for the treatment of cancer, either as a single agent or in combination with existing cancer treatment is warranted.

Epstein-Barr virus-associated gastric adenocarcinoma in Taiwan

Fifty-five gastric carcinoma tumors from Chinese patients in Taiwan, including 40 tubular type (one lymphoepthelioma-like carcinoma subtype), eight signet ring cell type, one papillary type, and six mucinous type gastric carcinomas, were investigated for the presence of Epstein-Barr virus (EBV) transcripts by in situ hybridization using fluorescein-conjugated EBV oligonucleotides for EBERs (Epstein-Barr virus early RNAs) expression and the polymerase chain reaction for viral DNA. Epstein-Barr virus was detected in six of 55 lesions (11%), a significantly lower proportion than has been observed in a North American series. Epstein-Barr virus involvement was more common among male patients. Epstein-Barr virus DNA and its EBERs were specifically present within gastric carcinoma and adjacent dysplastic cells but were absent in surrounding lymphocytes and normal gastric mucosa. Epstein-Barr virus DNA and EBERs were found in one sample of lymphoepithelioma-like carcinoma (LELC) and five specimens of typical gastric adenocarcinoma. Among the EBV-positive gastric adenocarcinomas, four were tubular type of varied differentiation and one was signet ring cell type. Furthermore, we evaluated the expression of the latent membrane protein (LMP) with monoclonal antibodies. We found that LMP was expressed in two EBV-positive samples. In addition, the presence of the EBV receptor was studied by probing samples with CD21 monoclonal antibody. Epstein-Barr virus receptor was not detected in any sample. Southern blot analysis indicated single clonal proliferation of tumor cells. These findings confirm and extend the results of Shibata et al. They also indicate that EBV infection might be related to oncogenesis not only in rare gastric cancers that resemble nasopharyngeal lymphoepithelioma but also in typical gastric adenocarcinoma.

Novel Phosphoinositide 3-Kinase/mTOR Dual Inhibitor, NVP-BGT226, Displays Potent Growth-Inhibitory Activity against Human Head and Neck Cancer Cells In Vitro and In Vivo

Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway frequently accounts for the tumorigenesis in head and neck cancer. To develop a new treatment, we investigated the effect of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in head and neck cancer cells. Experimental Design: The in vitro antitumor effect of BGT226 was determined in various cancer cell lines. Animal models were also applied to examine drug potency. The inhibitory ability of BGT226 on the PI3K/AKT/mTOR signaling pathway was analyzed. Results: The growth inhibition assay revealed that BGT226 was active against all tested cancer cell lines. Cross-resistance was not observed in the cisplatin-resistant cell line. The activation of the AKT/mTOR signal cascade was suppressed by BGT226 in a concentration- and time-dependent manner. Flow cytometric analysis revealed an accumulation of cells in the G0–G1 phase with concomitant loss in the S-phase. Results of the terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) assay and the analysis of caspase 3/7 and PARP indicated that BGT226 induced cancer cell death through an apoptosis-independent pathway. BGT226 induced autophagy as indicated by the aggregation and upregulation of the microtubule-associated protein light chain 3B-II, and p62 degradation. Gene silencing of Beclin1 or cotreatment of the autophagosome inhibitor, 3-methyladenine, inhibited the BGT226-induced autophagy and led to the retrieval of colony survival. In a xenografted animal model, BGT226 significantly delayed tumor growth in a dose-dependent manner, along with suppressed cytoplasmic expression of p-p70 S6 kinase and the presence of autophagosome formation. Conclusions: These data indicate that BGT226 is a potential drug in the treatment of head and neck cancer. Clin Cancer Res; 17(22); 7116–26. ©2011 AACR.

Phase II study of weekly oxaliplatin and 24-h infusion of high-dose 5-fluorouracil and folinic acid in the treatment of advanced gastric cancer

To investigate the efficacy and safety of combining weekly oxaliplatin with weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and folinic acid (FA) in treatment of patients with advanced gastric cancer. Patients with histologically confirmed, locally advanced or recurrent/metastatic gastric cancer were studied. Oxaliplatin 65 mg m−2 2-h intravenous infusion, and 5-FU 2600 mg m−2 plus FA 300 mg m−2 24-h intravenous infusion, were given on days 1 and 8, repeated every 3 weeks. Between January 2001 through January 2002, 55 patients were enrolled. The median age was 64 years (range: 22–75). In all, 52 patients (94.5%) had recurrent or metastatic disease and three patients had locally advanced disease. Among 50 patients evaluable for tumour response, 28 patients achieved partial response, with an overall response rate of 56% (95% confidence interval (CI): 41.8–70.3%). All 55 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 5.2 and 10.0 months, respectively, during median follow-up time of 24.0 months. Major grades 3–4 toxicities were neutropenia in 23 cycles (7.1%) and thrombocytopenia in 16 cycles (5.0%). Treatment was discontinued for treatment-related toxicities in nine patients (16.4%), of whom eight were due to oxaliplatin-related neurotoxicity. One patient (1.8%) died of neutropenic sepsis. This oxaliplatin-containing regimen is effective in the treatment of advanced gastric cancer. Except for neurotoxicity that often develops after prolonged use of oxaliplatin, the regimen is well tolerated.

Recent Advances in Anti-Survivin Treatments for Cancer

Apoptosis occurs via extrinsic or intrinsic signalling each triggered and regulated by many different molecular pathways. In recent years, the selective induction of apoptosis through survivin in tumour cells has been increasingly recognized as a promising approach for cancer therapy. Survivin has multiple functions including cytoprotection, inhibition of cell death, and cell-cycle regulation, especially at the mitotic process stage, all of which favour cancer survival. Many studies on clinical specimens have shown that survivin over expression is invariably up regulated in human cancers, associated with resistance to chemotherapy or radiation therapy, and linked to poor prognosis, suggesting that cancer cells survive with survivin. On the basis of these findings, survivin has been proposed as an attractive target for new anticancer interventions. Survivin inhibitors recently entered clinical trials. Recent studies suggest a possible role for survivin in regulating the function of normal adult cells. However, the expression and function of survivin in normal tissues are still not well characterized and understood. Still better understandings of survivins role in tumour versus normal cells are needed for designing the strategies to selectively disrupt survivin in cancers. In the present review, we summarise the importance of recent survivin-targeted cancer therapy for future clinical application.

Survivin – biology and potential as a therapeutic target in oncology

Survivin is a member of the inhibitor-of-apoptosis proteins (IAPs) family; its overexpression has been widely demonstrated to occur in various types of cancer. Overexpression of survivin also correlates with tumor progression and induces anticancer drug resistance. Interestingly, recent studies reveal that survivin exhibits multiple pro-mitotic and anti-apoptotic functions; the differential functions of survivin seem to be caused by differential subcellular localization, phosphorylation, and acetylation of this molecule. In this review, the complex expression regulations and post-translational modifications of survivin are discussed. This review also discusses how recent discoveries improve our understanding of survivin biology and also create opportunities for developing differential-functioned survivin-targeted therapy. Databases such as PubMed, Scopus® (Elsevier, New York, NY, USA), and SciFinder® (CAS, Columbus, OH, USA) were used to search for literature in the preparation of this review.

Synthesis and evaluation of 3-aroylindoles as anticancer agents: metabolite approach.

BPR0L075 (2) is a potential anticancer drug candidate designed from Combretastatin A-4 (1) based on the bioisosterism principle. Metabolites of 2, proposed from in vitro human microsome studies, were synthesized, leading to the identification of metabolite-derived analogue 10 with 40-350 pM potency against various cancer cell lines. Insights gained from the major inactive metabolite of 2 led to the development of 29, with better pharmacokinetics and improved potency in the tumor xenograft model than 2.

Antitubulin agents for the treatment of cancer – a medicinal chemistry update

The antitubulin agents taxanes and Vinca alkaloids form the first-line of treatment in clinical oncology for many cancers. The crucial role of microtubules in cell division has made antitubulin agents the focus of research, with sustained efforts to find new agents and to improve the profile of known agents by overcoming multi-drug resistance (MDR) and improving the druggability. The present review updates the medicinal chemistry of antitubulin agents covering the patents and literature published from May 2002 to November 2005. The antitubulin agents have been broadly classified into microtubule-destabilising agents, microtubule-stabilising agents and kinesin-like spindle protein inhibitors. This review provides an insight into the diversity of the chemical classes with antitubulin mechanisms of anticancer activity.

Menadione-induced DNA damage in a human tumor cell line

The nature and extent of menadione (MD)-induced DNA damage were explored using the human breast cancer cell line MCF-7. Concentration-dependent single-strand (ss) and double-strand (ds) DNA breaks were detected in MD-treated MCF-7 cells using the alkaline- and neutral-elution techniques, respectively. The repair of ss and ds DNA breaks was extensive but not complete after a 6-hr incubation in drug-free medium. Evidence was found for the production of DNA interstrand cross-links in MCF-7 cells treated with the bifunctional alkylating agent, mitomycin C, but not for cells treated with MD. Exposure of MCF-7 cells to etoposide (VP-16), mitoxantrone and camptothecin resulted in the detection of significant amounts of protein-linked DNA breaks, whereas none were found in MD-treated cells. These results support the proposition that MD-induced DNA damage is not likely to be mediated via topoisomerases, nor do significant amounts of protein-linked DNA form in MD-treated cells. Thus, MD serves as a good model for examination of the role of the quinone moiety in DNA damage in relation to redox cycling. Future studies directed at elucidation of the biochemical determinants mediating formation of reactive oxygen species effecting the MD-induced DNA damage are necessary and underway.

Discovery of 4-amino and 4-hydroxy-1-aroylindoles as potent tubulin polymerization inhibitors

1-Aroylindoline, 1-aroyl-1,2,3,4-tetrahydroquinoline, and 1-aroylindole derivatives were synthesized and evaluated for anticancer activity. The 4-amino and 4-hydroxy-1-aroylindoles 26 and 27 with IC 50 of 0.9 and 0.6 microM, respectively, exhibited antitubulin activity superior or comparable to that of colchicine and combretastatin A-4. They also showed antiproliferative activity with IC 50 of 0.3-5.4 nM in a set of human cancer cell lines.